Aspirin, ibuprofen, and reduced risk of advanced colorectal adenoma incidence and recurrence and colorectal cancer in the PLCO Cancer Screening Trial

BACKGROUND: Studying the differential impact of aspirin and other nonsteroidal anti-inflammatory drugs across the stages of colorectal neoplasia from early adenoma to cancer is critical for understanding the benefits of these widely used drugs. METHODS: With 13 years of follow-up, the authors prospectively evaluated the association between aspirin and ibuprofen use and incident distal adenoma (1221 cases), recurrent adenoma (862 cases), and incident colorectal cancer (CRC; 2826 cases) among men and women in the population-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. With multivariable-adjusted models, odds ratio (ORs) and 95% confidence intervals (CIs) for adenoma incidence and recurrence and hazard ratios (HRs) and 95% CIs for incident CRC were determined. RESULTS: The authors observed a significantly reduced risk of incident adenoma with ibuprofen use (≥30 vs \u3c4 pills per month: OR, 0.76 [95% CI, 0.60-0.95]; P(trend) = .04), particularly advanced adenoma (OR, 0.48 [95% CI, 0.28-0.83]; P(trend) = .005). Among those with a previous adenoma detected through screening, aspirin use was associated with a decreased risk of advanced recurrent adenoma (≥30 vs \u3c4 pills per month: OR, 0.56 [95% CI, 0.36-0.87]; P(trend) = 0.006). Both aspirin (HR, 0.88 [95% CI, 0.81-0.96]; P(trend) \u3c.0001) and ibuprofen use (HR, 0.81 [95% CI, 0.70-0.93); P(trend) = 0.003) ≥30 versus \u3c4 pills per month were significantly associated with reduced CRC risk. CONCLUSIONS: In this large prospective study with long-term follow-up, a beneficial role for not only aspirin, but also ibuprofen, in preventing advanced adenoma and curbing progression to recurrence and cancer among older adults was observed

Lentiviral-mediated gene transfer to the sheep brain: Implications for gene therapy in batten disease

The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are inherited neurodegenerative lysosomal storage diseases with common clinical features of blindness and seizures culminating in premature death. Gene-therapy strategies for these diseases depend on whether the missing activity is a secreted lysosomal protein taken up by neighboring cells, or an intramembrane protein that requires careful targeting. Therapies are best developed in animal models with large complex human-like brains. Lentiviral-mediated gene delivery to neural cell cultures from normal sheep and sheep affected with an NCL resulted in green fluorescent protein (GFP) expression in neurons and neuroblasts, more efficiently than in astrocytes. Similar transgene expression was obtained from two constitutive promoters, the viral MND promoter and the human EF1α promoter. In vivo studies showed stable and persistent GFP expression throughout the cell bodies, axons, and dendrites from intracortical injections and indicated ependymal and subependymal transduction. The sheep showed no ill effects from the injections. These data support continuing gene-therapy trials in the sheep models of Batten disease

Body composition changes during 8 weeks of military training are not accurately captured by circumference-based assessments

In 1981, the US military adopted body fat standards to promote physical readiness and prevent obesity. Separate circumference-based equations were developed for women and men. Both predictive equations were known to underestimate %BF. However, it was not known how well these abdominal circumference-based methods tracked changes in %BF. This study examined the validity of the circumference-based %BF equations for assessing changes in %BF in young adult recruits during Army Basic Combat Training (BCT). Dual-energy X-ray absorptiometry (DXA) and circumference-based measures of %BF were obtained in women (n = 481) and men (n = 926) at the start (pre-BCT) and end (post-BCT) of 8 weeks of BCT. Repeated-measure ANOVAs were used to assess differences between DXA and circumference pre-BCT and for the change during BCT. Pre-BCT, circumferences underestimated %BF relative to DXA, with mean errors of −6.0% ± 4.4% for women and −6.0% ± 3.5% for men (both p < 0.01), and no difference between sexes was observed (p = 0.77). DXA detected a −4.0% ± 2.4% and −3.3% ± 2.8% change in %BF for women and men in response to BCT, respectively (both p < 0.01), whereas circumference estimates of %BF indicated a 0.0% ± 3.3% (p = 0.86) change in women and a −2.2% ± 3.3% (p < 0.01) change in men (sex difference by technique p < 0.01). In conclusion, circumference-based measures underestimated %BF at the start of BCT in both sexes as compared to DXA. Circumference measures underestimated changes in %BF during BCT in men and did not detect changes in women. These findings suggest that circumference-based %BF metrics may not be an appropriate tool to track changes in body composition during short duration training

Film as architectural theory

Publications on architectural theory have predominantly taken on the form of text-based books, monographs, and articles. With the rise of transdisciplinary and practice-based research in architecture, new opportunities are opening up for other forms of architectural theory, such as film-based mediums, which promise to expand and alter the convention of the written practice of theory. Two possible types of filmic theory are presented here. One follows the method of ethnographic documentary filmmaking inspired by Sarah Pinkfilm-based mediums, which promise to expand and alter thellows the line of art house filmmaking inspired by Kathryn Rameyyn Rameyg inspired by Sarah Pinkfilm-based mediums, which promise to expand ae to expand ad mediums, which promise to expand a convention of the written practice of theory. or constructing knowledge, new discourses on filmic theory can be opened up. It is argued here that film as architectural theory is part of this new discourse, broadening the audience’u engagement with architecture through not only “readership” but also “viewership.

Genetic Variation in Base Excision Repair Pathway Genes, Pesticide Exposure, and Prostate Cancer Risk

Background: Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC